Contribution of Inbred Singletons to Variance Component Estimation of Heritability and Linkage

Objectives: An interesting consequence of consanguinity is that the inbred singleton becomes informative for genetic variance. We determine the contribution of an inbred singleton to variance component analysis of heritability and linkage. Methods: Statistical theory for the power of variance component analysis of quantitative traits is used to determine the expected contribution of an inbred singleton to likelihood-ratio tests of heritability and linkage. Results: In variance component models an inbred singleton contributes relatively little to a test of heritability, but can contribute substantively to a test of linkage. For small to moderate QTL effects and a level of inbreeding comparable to matings between first cousins (the preferred form of union in many human populations), an inbred singleton can carry nearly 25% the information of a non-inbred sibpair. In more highly inbred contexts available with experimental animal populations, nonhuman primate colonies, and some human subpopulations, the contribution of an inbred singleton relative to a sibpair can exceed 50%. Conclusions: Inbred individuals, even in isolation from other members of a sample, can contribute to variance component estimation and tests of heritability and linkage. Under certain conditions the informativeness of the inbred singleton can approach that of non-inbred sibpair

Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance

Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based test results, protein-protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR\u3c0.1, association was detected for rs10941112 (P=2.1×10−5; q-value=0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (P=5.5×10−4), including brain tissue data from the Genotype-Tissue Expression project (minimum P=6.0×10−5). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (P=2.8×10−5; q-value=0.073). Protein-protein interactions among our top gene-based association results (P\u3c0.05; n=359 genes) reveal significant enrichment of genes involved in NCAM-mediated neurite outgrowth (P=3.0×10−5), while exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase-mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance

Spectral Reflectance Can Differentiate Tracheal and Esophageal Tissue in the Presence of Bodily Fluids and Soot

Endotracheal intubation is a common life-saving procedure implemented in emergency care to ensure patient oxygenation, but it is difficult and often performed in suboptimal conditions leading to high rates of patient complications. Undetected misplacement in the esophagus is a preventable complication that can lead to fatalities in 5–10% of patients who undergo emergency intubation. End-tidal carbon dioxide monitoring and other proper placement detection methods are useful, yet the problem of misplacement persists. Our previous work demonstrated the utility of spectral reflectance sensors for differentiating esophageal and tracheal tissues, which can be used to confirm proper endotracheal tube placement. In this study, we examine the effectiveness of spectral characterization in the presence of saline, blood, “vomit”, and soot in the trachea. Our results show that spectral properties of the trachea that differentiate it from the esophagus persist in the presence of these substances. This work further confirms the potential usefulness of this novel detection technology in field applications

Spectral Reflectance as a Unique Tissue Identifier in Healthy Humans and Inhalation Injury Subjects

Tracheal intubation is the preferred method of airway management, a common emergency trauma medicine problem. Currently, methods for confirming tracheal tube placement are lacking, and we propose a novel technology, spectral reflectance, which may be incorporated into the tracheal tube for verification of placement. Previous work demonstrated a unique spectral profile in the trachea, which allowed differentiation from esophageal tissue in ex vivo swine, in vivo swine, and human cadavers. The goal of this study is to determine if spectral reflectance can differentiate between trachea and other airway tissues in living humans and whether the unique tracheal spectral profile persists in the presence of an inhalation injury. Reflectance spectra were captured using a custom fiber-optic probe from the buccal mucosa, posterior oropharynx, and trachea of healthy humans intubated for third molar extraction and from the trachea of patients admitted to a burn intensive care unit with and without inhalation injury. Using ratio comparisons, we found that the tracheal spectral profile was significantly different from buccal mucosa or posterior oropharynx, but the area under the curve values are not high enough to be used clinically. In addition, inhalation injury did not significantly alter the spectral reflectance of the trachea. Further studies are needed to determine the utility of this technology in a clinical setting and to develop an algorithm for tissue differentiation

Genotype phasing in pedigrees using whole-genome sequence data

Phasing is the process of inferring haplotypes from genotype data. Efficient algorithms and associated software for accurate phasing in pedigrees are needed, especially for populations lacking reference panels of sequenced individuals. We present a novel method for phasing genotypes from whole-genome sequence data in pedigrees, called PULSAR (Phasing Using Lineage Specific Alleles/Rare variants). The method is based on the property that alleles specific to a single founding chromosome within a pedigree are highly informative for identifying haplotypes that are shared identical by descent. Simulation studies are used to assess the performance of PULSAR with various pedigree sizes and structures, and the effect of genotyping errors and the presence of nonsequenced individuals is investigated. In pedigrees with complete sequencing and realistic genotyping error rates, PULSAR correctly phases \u3e99.9% of heterozygous genotypes, excluding sites at which all individuals are heterozygous, and does so with a switch error rate frequently below 10−4. PULSAR is highly accurate, capable of genotype error correction and imputation, and computationally competitive with alternative phasing software applicable to pedigrees. Our method has the significant advantage of not requiring reference panels that are essential for other population-based phasing algorithms. A software implementation of PULSAR is freely available

Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk

Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32-35.3, we analyzed 407 protein-altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders